We have established murine models in which monoclonal antibody (McAb) directed at Thy 1.2 inhibits proliferation of the A strain leukemia, ASL.l, both in vitro and when transplanted into congenic A/Thy 1.1 hosts (90% cures). The objectives of the proposed research are: 1) to define the mechanism(s) by which McAb curtails tumor growth, 2) to estalilsh means of increasing the effectiveness of McAb-therapy and 3) to evaluate the susceptibility of priumary tumors to McAb that controls transplanted lkeukemias. Based on previous experiments, emphasis will be placed on investigating the protential contributions of antibody dependent cellular cytotoxicity and/or direct interaction of McAb with the target cell membrane to tumor cell regulation. To determine whether it is possible that ADCC plays a role in McAb-therapy, will use F (ab')2 antibody fragment which lack in vitro ADCC activity. If these F(ab')2 also lack therapeutic effects, we will investigate ADCC further. Therapy trials will be performed in mice with functional deficiencies (genetic, age-related, or pharmacologically-induced). To further characterize/identify putative effector systems, transfers of selected cell populations will be used to restore responsiveness to therapy. Preliminary experiments on cultured ASL.1 cells have shown that low density cultures are sensiative to inhibition of proliferation by McAb. Flow cytometric analyses will show wheter sensitivity to McAb varies with the cell cycle, and if so, whether this is attributable to changes in antigen expression at the cell surface. Results of these experiments will be used to design more effective therapy protocols (i.e. "push back" previously defined limitations). The following approaches will be considered: 1) attempt to increase the crucial host effector function 2) attempt to manipulate the tumor cells into an antibody-sensitive phase of the cell cycle, and 3) attempt to effect synergistic tumor cell kill without increased systemic toxicity by combining antibody with conventional chemotherapeutic drugs.